Epidemiology Table of Contents UNIT ONE: Introduction to Epidemiology.......... Objectives................................................... Definition.................................................... v • Introduction............................................................ Acknowledgement................................................. • UNIT ONE: Introduction to Epidemiology.......... o Objectives...................................................  Definition....................................................  History of Epidemiology..............................  Purpose/Use of Epidemiology.................... o Exercise...................................................... • UNIT TWO: Disease Causation............................ o Objective.................................................... o Definition.................................................... o Causes of disease...................................... o Exercise.................................................... • UNIT THREE: Levels of prevention................... o Objectives................................................. o Natural history of disease......................... o Measurements of morbidity...................... o Measurements of Mortality....................... o Exercise:................................................... o data collection......................................... UNIT SEVEN: Sources of Data and methods of o Objectives:................................................ o Sources of data........................................ o Exercise:...................................................  Management........................................... UNIT EIGHT: Epidemic Investigation and  Objectives................................................ o Levels of Disease Occurrence.................. o Types of epidemics................................... o Investigation of an Epidemic..................... o Exercise.................................................... • UNIT NINE: Epidemiological Surveillance........ o Objectives................................................. • Definition.................................................. • Purpose of surveillance............................ • Types of surveillance................................ • Activities in Surveillance........................... • Features of a good surveillance system.... • The integrated disease surveillance system • Exercise.................................................... • Reference................................................ Introduction to Epidemiology Learning Objectives: At the end of this unit the student is expected to:  Define Epidemiology  Identify the main issues in the definition  Discuss the uses of Epidemiology 1. Definition Epidemiology is the study of the frequency, distribution and determinants of diseases and other health related conditions in human populations, and the application of this study to the promotion of health, and to the prevention

1. Chem 454: Regulatory Mechanisms in Biochemistry
University of Wisconsin-Eau Claire
Lecture 12 - Nucleotide
Biosynthesis

2. 2
Nucleotides perform a wide variety of
functions
Building blocks for nucleic acids
Universal energy carriers (ATP, GTP)
Activators (e.g. UDP-glucose)
Components of signal transduction pathways (cAMP,
cGMP)
Nucleotides contain
Ribose or deoxyribose sugar
One to three phosphate groups
purine or pyrimidine hetercyclic nitrogen base.
Introduction

3. 3
We will focus on the nucleotide bases
Glycine and aspartate will provide a carbon
scaffold.
Aspartate and glutamine will provide the nitrogen.
We will look at
de novo synthesis of pyrimidine bases
de novo synthesis of purines bases
Synthesis of deoxyribonucleotides
Regulation of nucleotide synthesis
Introductions

4. 4
de Novo versus salvage pathways
Introduction

5. 5
Nomenclature
Introduction

6. 6
The ring is assembled
from bicarbonate,
aspartate and
glutamate.
The ring is synthesized
first and then added to
the ribose.
The ammonia is produced
from the hydrolysis of
glutamine
1. de Novo Synthesis of Pyrimidines

7. 7
Carbarmoyl phosphate is synthesized from
bacarbonate and ammonia
1.1 Pyrimidine Synthesis, First Step

8. 8
Carbamoyl
phosphate
synthetate
1.1 Pyrimidine Synthesis, First Step

9. 9
Carbamoyl phosphate
synthetase also contains
a glutamine hydrolysis
domain
1.2 Glutamine Hydrolysis

10. 10
The ammonia is
channeled 45Å to the
carboxyphosphate
The carbamic acid is
channeled another
35Å to the site where
it is phosphorylated
1.3 Substrate Channeling

11. 11
Synthesis of Orotate and attachment to
ribose ring.
The first reaction is catalyzed by aspartate
transcarbamylase
1.4 Pyrimidine Synthesis, Second Step

12. 12
Synthesis of Orotate
and attachment to
ribose ring.
Reaction is driven by
the hydorlysis of
pyrophosphate
1.4 Pyrimidine Synthesis, Second Step

13. 13
Decarboxylation of orotidylate produces
uridylate
1.4 Pyrimidine Synthesis, Second Step

14. 14
Nucleotide mono-, di-, and triphospahtes are
interconvertible
Nucleoside monophosphate kinases
UMP is converted to UTP before going on to produce
CTP
1.5 Nucleotides

15. 15
CTP is formed by amination (not animation!)
of UTP.
1.6 CTP

16. 16
Salvage versus de
Novo synthesis
2. de Novo Synthesis of Purines

17. 17
The purine ring system is assembled on a
ribose phosphate.
glutamine phosphoribosyl amidotransferase
2.2 Purines Synthesis, Step One

18. 18
The purine ring is assembled by successive
steps of activation by phosphorylation,
followed by displacement.
2.3 Purine Ring Synthesis

19. 19
2.3 Purine Ring Synthesis

20. 20
2.3 Purine Ring Synthesis

21. 21
AMP and GMP are formed from IMP
2.4 AMP and GMP

22. 22
Deoxyribonucleotides are produced form
either ribonucleotide di- or triphophosphates
The 2'-OH on the ribose sugar is reduced to a
hydrogen.
NADPH + H+
is the reducing agent.
The enzyme is called ribonucleotide reductase
3. Deoxyribonucleotides

23. 23
Ribonucleotide reductase
R1 (87 kD dimer)
active site
allosteric sites
R2 (43 kD dimer)
3. Deoxyribonucleotides

24. 24
Ribonucleotide reductase: R1 subunit
3. Deoxyribonucleotides

25. 25
Ribonucleotide reductase: R2 subunit
3. Deoxyribonucleotides

26. 26
Ribonucleotide reductase
1. Transfer of a electron from a cysteine on R1 to
the tyrosyl radical on R2
3. Deoxyribonucleotides

27. 27
Ribonucleotide reductase
2. The cysteine thiyl radical produced on R1
abstracts a hydrogen from the C-3' of the ribose
unit.
3. Deoxyribonucleotides

28. 28
Ribonucleotide reductase
3. The carbon radical at C-3'
promotes the release of a
hydorxide ion on carbon-2.
3. Deoxyribonucleotides

29. 29
Ribonucleotide reductase
4. Hydride is transfered from a third cysteine
residue to complete the reduction of the C–2'
position.
3. Deoxyribonucleotides

30. 30
Ribonucleotide reductase
5. The C–3' radical recaptures the hydrogen that
was abstracted by the first cysteine residue.
3. Deoxyribonucleotides

31. 31
Ribonucleotide reductase
6. The tyrosyl free radical is
regenerated
3. Deoxyribonucleotides

32. 32
Ribonucleotide reductase
7. The disulfide is reduced by thioredoxin.
8. Thioredoxin is reduced by thioredoxin reductase
using NADH + H+
3. Deoxyribonucleotides

33. 33
3.1 Thymidylated Formed by
Methylation

34. 34
3.2 Dihydrofolate Reductase

35. 35
3.3 Anticancer Drugs
Inhibition of the synthesis of
dexoyribonucleotides or thymidylate will
selectively inhibit fast growing cells.

36. 36
4. Regulation of Nucleotide
Biosynthesis

37. 37
5. NAD+, FAD and Coenzyme A
(Skip)

38. 38
6. Metabolic Diseases (Skip)

39. 39
6.1 Purine Degradation (Skip)

40. 40
6.2 Lesch-Nyhan Syndrome (Skip)